Prognostic Value of Germline Copy Number Variants and Environmental Exposures in Non-small Cell Lung Cancer

Germline copy number variant (gCNV) has been studied as a genetic determinant for prognosis of several types of cancer, but little is known about how it affects non-small cell lung cancer (NSCLC) prognosis. We aimed to develop a prognostic nomogram for NSCLC based on gCNVs. Promising gCNVs that are associated with overall survival (OS) of NSCLC were sorted by analyzing the TCGA data and were validated in a small Chinese population. Then the successfully verified gCNVs were determined in a training cohort (n = 570) to develop a prognostic nomogram, and in a validation cohort (n = 465) to validate the nomogram. Thirty-five OS-related gCNVs were sorted and were reduced to 15 predictors by the Lasso regression analysis. Of them, only CNVR395.1 and CNVR2239.1 were confirmed to be associated with OS of NSCLC in the Chinese population. High polygenic risk score (PRS), which was calculated by the hazard effects of CNVR395.1 and CNVR2239.1, exerted a significantly higher death rate in the training cohort (HR = 1.41, 95%CI: 1.16–1.74) and validation cohort (HR = 1.42, 95%CI: 1.13–1.77) than low PRS. The nomogram incorporating PRS and surrounding factors, achieved admissible concordance indexes of 0.678 (95%CI: 0.664–0.693) and 0.686 (95%CI: 0.670–0.702) in predicting OS in the training and validation cohorts, respectively, and had well-fitted calibration curves. Moreover, an interaction between PRS and asbestos exposure was observed on affecting OS (Pinteraction = 0.042). Our analysis developed a nomogram that achieved an admissible prediction of NSCLC survival, which would be beneficial to the personalized intervention of NSCLC

Integrative analysis to identify oncogenic gene expression changes associated with copy number variations of enhancer in ovarian cancer

Enhancers are short regulatory regions (50-1500 bp) of DNA that control the tissue-specific activation of gene expression by long distance interaction with targeting gene regions. Recently, genome-wide identification of enhancers in diverse tissues and cell lines was achieved using high-throughput sequencing. Enhancers have been associated with malfunctions in cancer development resulting from point mutations in regulatory regions. However, the potential impact of copy number variations (CNVs) on enhancer regions is unknown. To learn more about the relationship between enhancers and cancer, we integrated the CNVs data on enhancers and explored their targeting gene expression pattern in high-grade ovarian cancer. Using human enhancer-gene interaction data with 13,691 interaction pairs between 7,905 enhancers and 5,297 targeting genes, we found that the 2,910 copy number gain events of enhancer are significantly correlated with the up-regulation of targeting genes. We further identified that a number of highly mutated superenhancers, with concordant gene expression change on their targeting genes. We also identified 18 targeting genes by super-enhancers with prognostic significance for ovarian cancer, such as the tumour suppressor CDKN1B. We are the first to report that abundant copy number variations on enhancers could change the expression of their targeting genes which would be valuable for the design of enhancer-based cancer treatment strategy. © Li et al

Changes in COVID-19 vaccine hesitancy at different times among residents in Guangzhou, China

BackgroundVaccination as a fundamental pillar of promoting public health and interest is critical to limiting the COVID-19 pandemic. However, many citizens are still hesitant about this epidemic prevention measure. This article aimed to understand the COVID-19 vaccination and hesitancy rates among Guangzhou residents at different points in time as well as to explore the relevant factors that cause vaccination hesitancy.MethodsWe conducted a total of nine cross-sectional surveys by enrolling 12,977 questionnaires among Guangzhou residents through the online survey software called “WenJuanXing” between April 2021 and December 2022, and residents made their choices by judging their willingness to vaccinate. These surveys collected data on the participants' sociodemographic characteristics, vaccination status, vaccine hesitancy, and factors influencing this hesitancy. The Chi-squared test was used for univariate analysis and the multivariate logistic regression model was used to further adjust the influence of the confounding factors to evaluate the main factors affecting the hesitancy of the COVID-19 vaccine at different periods.ResultsOver the course of 2021–2022, a total of 12,977 residents in the study area were surveyed. The vaccine hesitancy rates fluctuated over time. From April to June 2021, the vaccine hesitancy rate decreased from 30% to 9.1% and then increased to 13.7% in November. However, from April to December 2022, the hesitancy rate continued to rise from 13.4% to 30.4%. Vaccination rates, the epidemic waves of COVID-19, and changes in policies may all be possible factors that contributed to these fluctuations in vaccine hesitancy rates. We found statistically significant correlations between factors, such as residence, education, and occupation, and vaccine hesitancy at certain points of time. The results of the surveys in April and June 2021 showed that rural residents showed higher vaccine hesitancy rate than urban residents. Their lower education level was associated with higher vaccine hesitancy. Workers and farmers are more likely to have vaccine hesitancy than people with other occupations. The univariate analysis showed that people with underlying medical conditions and lower perceived health status were more likely to experience vaccine hesitation. Logistic regression analysis revealed that the health status of individuals is the most important factor leading to vaccine hesitancy, and residents' underestimation of domestic risks and overconfidence in personal protection measures were also contributing factors. At different stages, vaccine hesitancy among residents was related to vaccine side effects, safety and efficacy, convenience fluctuation, and various factors.ConclusionIn the present study, we found that vaccine hesitancy did not display a consistent downward trend but it fluctuated over time. Higher education, residing in urban areas, lower perceived disease risk, and concerns about the vaccine's safety and side effects were risk factors for vaccine hesitancy. Implementing appropriate interventions and educational programs tailored to address these risk factors may prove to be effective in enhancing public confidence on vaccination

Identification of cancer-associated fibroblast signature genes for prognostic prediction in colorectal cancer

BackgroundCancer-associated fibroblasts are an essential part of the tumor immunoenvironment, playing key roles in malignancy progression and treatment response. This study was to characterize cancer-associated fibroblasts-related genes (CAFs) in colorectal cancer (CRC) and establish signature genes associated with CAF for prognosis prediction.MethodsWe downloaded single-cell RNA sequencing (scRNA-seq) data from the GEO database and bulk RNA-seq data from TCGA database to identify differentially expressed genes related to fibroblasts. In the TCGA set, DEGs were identified from tumor samples, and the WGCNA method was utilized to identify module genes. By comparing the WGCNA module genes with tumor fibroblast-related DEGs, we took the overlapped cohorts as crucial CAFs. Moreover, the prognostic CAFs were identified using univariate analysis. A CAFs risk model was established using the LASSO algorithm and then validated using external datasets. Ultimately, the expression of prognostic CAFs in CRC was confirmed using qRT-PCR.ResultsA large cohort of DEGs were identified as CAFs, with eight demonstrating prognostic significance. These CAFs were primarily related to seven pathways, including peroxisome function, B cell receptor signal, and cell adhesion molecule. The CAFs risk model exhibited high accuracy for predicting prognosis, as confirmed through validation using external independent cohorts. Additionally, the risk signature showed significant correlations with immune-related scores, tumor purity, estimate, and stromal scores. qRT-PCR validated that the expression level of RAB36 was significantly downregulated in the HCT116 and HT29 cell lines compared to the NCM460 cells. Conversely, CD177, PBX4 and CCDC78 were upregulated in the HCT116 and HT29 cell lines, and ACSL6 and KCNJ14 only in HCT116 cells (P < 0.05). The expression trends of CD177 and CCDC78 were consistent with our predicted results.ConclusionThe CAFs risk model accurately predicted prognosis, immune cell infiltration, and stromal estimates. The prognostic CAFs (CD177 and CCDC78) may be potential therapeutic targets for CRC

Polymorphisms of<i>NF<i>κ</i>B1</i>and<i>I<i>κ</i>B<i>α</i></i>and Their Synergistic Effect on Nasopharyngeal Carcinoma Susceptibility

Nasopharyngeal carcinoma (NPC) is a multifactoral and polygenic disease with high prevalence in Southeast Asia and Southern China. Environmental factors and genetic susceptibility play important roles in NPC pathogenesis. In the present study, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in nuclear factor-kappa B (NFκB) and its inhibitor (IκBα) conferred consistent risks for NPC. Four putatively functional SNPs (NFκB1: rs28362491del&gt;ins ATTG;NFκB2: rs12769316G&gt;A;IκBα: rs2233406C&gt;T and rs696G&gt;A) were analyzed to evaluate their associations with NPC risk in total 1590 NPC cases and 1979 cancer-free controls. We found that the rs28362491 insATTG variants (ins/del + ins/ins) inNFκB1conferred an increased risk of NPC (odds ratio[OR]=1.30, 95% confidence interval[CI]=1.09–1.55, andP=2.80×10-3) compared with the del/del homozygous genotype. The rs696AA variant inIκBαhad an increased risk of NPC (OR=1.41, 95% CI=1.20–1.66, andP=2.28×10-5) by decreasingIκBαexpression due to the modulation of microRNA hsa-miR-449a. Furthermore, both adverse genotypes ofNFκB/IκBαand their interaction also exerted an increased risk on NPC. Taken together, Our findings indicated that genetic variants inNFκB1(rs28362491del&gt;ins ATTG) andIκBα(rs696G&gt;A) and their synergistic effect might contribute to NPC predisposition.</jats:p

Exploring the therapeutic mechanism of curcumin in spinal cord injury treatment based on network pharmacology, molecular dynamics simulation, and experimental validation

IntroductionCurcumin, a natural active compound derived from plants, is widely used as a pigment across the globe. Research has demonstrated that curcumin possesses neuroprotective properties in spinal cord injuries (SCIs); however, its specific mechanisms of action remain unclear. This study aimed to elucidate the potential mechanisms underlying curcumin’s therapeutic effects in SCI.MethodsWe screened the targets of curcumin in the treatment of spinal cord injury using network pharmacology across a variety of public databases. The interaction between the compound and the target was analyzed through bioinformatics analysis, molecular docking, and molecular dynamics simulation. Finally, the prediction results were verified by simulating spinal cord injury through oxygen–glucose deprivation (OGD) injury in PC12 cells.ResultsInitial screening indicated 13 core targets involved in mitigating SCI. Curcumin may regulate the HIF pathway, immune cells, inflammation, oxidative stress, and other processes. Matrix metalloproteinase-9 (MMP9), tumor necrosis factor (TNF), interleukin-1β (IL-1β), signal transducer and activator of transcription 3 (STAT3), and caspase 3 (CASP3) were identified as key targets of curcumin in SCI regulation. Molecular docking results demonstrated that curcumin exhibited favorable affinity with the core targets, with MMP9 showing the highest binding affinity (−8.76 kcal/mol). Further studies confirmed that curcumin stably binds with MMP9, and the binding site was located at residues 220–225. Cell counting kit-8 (CCK8) assay results showed that curcumin exerted a good therapeutic effect. Western blot results showed that curcumin inhibited the expression of MMP9 protein but had no significant effect on the expression of TNF-α.ConclusionCurcumin exerts its effects on SCI through multiple targets and pathways. Its specific mechanisms involve the inhibition of inflammation, prevention of apoptosis and ferroptosis, and promotion of neuronal repair. MMP9 may be a key target mediating curcumin’s protective effects against SCI. These findings provide scientific evidence for further research and development of drugs

A Functional Copy-Number Variation in MAPKAPK2 Predicts Risk and Prognosis of Lung Cancer

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) may promote cancer development and progression by inducing tumorigenesis and drug resistance. To assess whether the copy-number variation g.CNV-30450 located in the MAPKAPK2 promoter has any effect on lung cancer risk or prognosis, we investigated the association between g.CNV-30450 and cancer risk in three independent case-control studies of 2,332 individuals with lung cancer and 2,457 controls and the effects of g.CNV-30450 on cancer prognosis in 1,137 individuals with lung cancer with survival data in southern and eastern Chinese populations. We found that those subjects who had four copies of g.CNV-30450 had an increased cancer risk (odds ratio = 1.94, 95% confidence interval [CI] = 1.61–2.35) and a worse prognosis for individuals with lung cancer (with a median survival time of only 9 months) (hazard ratio = 1.47, 95% CI = 1.22–1.78) compared with those with two or three copies (with a median survival time of 14 months). Meanwhile, four copies of g.CNV-30450 significantly increased MAPKAPK2 expression, both in vitro and in vivo, compared with two or three copies. Our study establishes a robust association between the functional g.CNV-30450 in MAPKAPK2 and risk as well as prognosis of lung cancer, and it presents this functional copy-number variation as a potential biomarker for susceptibility to and prognosis for lung cancer

A Common Genetic Variant (97906C>A) of DAB2IP/AIP1 Is Associated with an Increased Risk and Early Onset of Lung Cancer in Chinese Males

DOC-2/DAB2 interactive protein (DAB2IP) is a novel identified tumor suppressor gene that inhibits cell growth and facilitates cell apoptosis. One genetic variant in DAB2IP gene was reported to be associated with an increased risk of aggressive prostate cancer recently. Since DAB2IP involves in the development of lung cancer and low expression of DAB2IP are observed in lung cancer, we hypothesized that the variations in DAB2IP gene can increase the genetic susceptibility to lung cancer. In a case-control study of 1056 lung cancer cases and 1056 sex and age frequency-matched cancer-free controls, we investigated the association between two common polymorphisms in DAB2IP gene (−1420T>G, rs7042542; 97906C>A, rs1571801) and the risk of lung cancer. We found that compared with the 97906CC genotypes, carriers of variant genotypes (97906AC+AA) had a significant increased risk of lung cancer (adjusted odds ratio [OR] = 1.33, 95%CI = 1.04–1.70, P = 0.023) and the number of variant (risk) allele worked in a dose-response manner (Ptrend = 0.0158). Further stratification analysis showed that the risk association was more pronounced in subjects aged less than 60 years old, males, non-smokers, non-drinkers, overweight groups and in those with family cancer history in first or second-degree relatives, and the 97906A interacted with overweight on lung cancer risk. We further found the number of risk alleles (97906A allele) were negatively correlated with early diagnosis age of lung cancer in male patients (P = 0.003). However, no significant association was observed on the −1420T>G polymorphism. Our data suggested that the 97906A variant genotypes are associated with the increased risk and early onset of lung cancer, particularly in males

Exposure to Polycyclic Aromatic Hydrocarbons, Plasma Cytokines, and Heart Rate Variability

Epidemiological studies have suggested associations between polycyclic aromatic hydrocarbons (PAHs) and heart rate variability (HRV). However, the roles of plasma cytokines in these associations are limited. In discovery stage of this study, we used Human Cytokine Antibody Arrays to examine differences in the concentrations of 280 plasma cytokines between 8 coke-oven workers and 16 community residents. We identified 19 cytokines with significant different expression (fold change ≥2 or ≤−2, and q-value 16% BDNF decreases. Additionally, OH-PAHs were positively associated with activated leukocyte cell adhesion molecule (ALCAM) and C-reactive protein (CRP) (p 20% increases in CRP. We also found significant associations between these cytokines and HRV (p 8% decreases in HRV. Our results indicated PAH exposure was associated with plasma cytokines, and higher cytokines were associated with decreased HRV, but additional human and potential mechanistic studies are needed